Research Article | Volume 13, Supplement 1, September, 2023

Identification of effective natural compounds as HIF-1Alpha mimetics for diabetic wound healing; A systematic in-silico study

Esakkimuthukumar Mariappan Akey Krishna Swaroop Preeya Negi Saranya RajanBabu Dhinesh Kumar Murugesan Nadimpalli Prudhvi Varma Jubie Selvaraj   

Open Access   

Published:  Sep 20, 2023

DOI: 10.7324/JAPS.2023.135162
Abstract

The Von Hippel-Lindau (VHL) E3 ubiquitin ligase is responsible for the degradation of hypoxia-inducible factor 1α (HIF-1α) under hydroxylation. Computer-aided drug design leads to the discovery of HIF-1α mimetics for the stabilization of hydroxylated α subunit of HIF-1α from subsequent proteasomal degradation to improve diabetic wound healing. The protein-protein interaction (PPI) networking confirms the interaction between the VHL—HIF-1α proteins. So, VHL is the potential target to stabilize the HIF-1α. A set of natural compounds as an inhibitor of PPI between VHL—HIF-1α is identified by structure-based virtual screening. The free HIF-1α leads to accelerates wound closure in both normal and diabetic conditions, with a more significant effect being observed in the diabetic condition. The natural products were designed as HIF-1α mimetics through in-silico Pharmacophore modeling followed by structure-based virtual screening and molecular simulation. In the pharmacophore modeling, 2 acceptors and 1 donor pharmacophore are generated. In the virtual screening process, generated pharmacophore gives a data set of natural compounds that have the same pharmacophoric feature. Based on the docking and absorption, distribution, metabolism, elimination, toxicity studies, the potential inhibitor (ZINC ID: ZINC15959407, ZINC12884117) of PPI is identified.


Keyword:     Natural compounds HIF-1α diabetic wound pharmacophore virtual screening impaired w


Citation:

Mariappan E, Swaroop AK, Negi P, RajanBabu S, Murugesan DK, Varma NP, Selvaraj J. Identification of effective natural compounds as HIF-1Alpha mimetics for diabetic wound healing; A systematic in-silico study. J Appl Pharm Sci, 2023; 13(Suppl 1):041–050. https://doi.org/10.7324/JAPS.2023.135162

Copyright: © The Author(s). This is an open-access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

HTML Full Text

Reference

Akkus G, Sert M. Diabetic foot ulcers: a devastating complication of diabetes mellitus continues non-stop in spite of new medical treatment modalities. World J Diabetes, 2022; 13(12):1106-21. https://doi.org/10.4239/wjd.v13.i12.1106

Beck J, Henschel C, Chou J, Lin A, Del Balzo U. Evaluation of the carcinogenic potential of roxadustat (FG-4592), a small molecule inhibitor of hypoxia-inducible factor prolyl hydroxylase in CD-1 mice and Sprague Dawley rats. Int J Toxicol, 2017; 36(6):427-39. https://doi.org/10.1177/1091581817737232

Dallakyan S, Olson AJ. Small-molecule library screening by docking with PyRx. Methods Mol Biol, 2015; 1263:243-50. https://doi.org/10.1007/978-1-4939-2269-7_19

Deng L, He S, Guo N, Tian W, Zhang W, Luo L. Molecular mechanisms of ferroptosis and relevance to inflammation. Inflamm Res, 2023; 72(2):281-99. https://doi.org/10.1007/s00011-022-01672-1

Esfahani M, Karimi F, Afshar S, Niknazar S, Sohrabi S, Najafi R. Prolyl hydroxylase inhibitors act as agents to enhance the efficiency of cell therapy. Expert Opin Biol Ther, 2015; 15(12):1739-55. https://doi.org/10.1517/14712598.2015.1084281

Esakkimuthukumar M, Swaroop AK, Patnaik SK, Kumar R R, T K P, Naik MR, S J. A novel family of small molecule HIF-1 alpha stabilizers for the treatment of diabetic wounds; an integrated in silico, in vitro, and in vivo strategy. RSC Adv, 2022; 12(48):31293-302. https://doi.org/10.1039/D2RA05364K

Guo S, Dipietro LA. Factors affecting wound healing. J Dent Res, 2010; 89(3):219-9. https://doi.org/10.1177/0022034509359125

Li W, Jiang L, Wu S, Yang S, Ren L, Cheng B , Xia J. A Shape-programmable hierarchical fibrous membrane composite system to promote wound healing in diabetic patients. Small, 2022; 18(11):e2107544. https://doi.org/10.1002/smll.202107544

Li G, Ko CN, Li D, Yang C, Wang W, Yang GJ, Di Primo C, Wong VKW, Xiang Y, Lin L, Ma DL, Leung CH. A small molecule HIF-1α stabilizer that accelerates diabetic wound healing. Nat Commun, 2021; 12(1):3363. https://doi.org/10.1038/s41467-021-23448-7

Jones S, Thornton JM. Principles of protein-protein interactions. Proc Natl Acad Sci, 1996; 93(1):13-20. https://doi.org/10.1073/pnas.93.1.13

Mohammed HA, Qureshi KA, Ali HM, Al-Omar MS, Khan O, Mohammed SAA. Bio-evaluation of the wound healing activity of Artemisia judaica L. as part of the plant's use in traditional medicine; phytochemical, antioxidant, anti-inflammatory, and antibiofilm properties of the plant's essential oils. Antioxidants (Basel), 2022; 11(2):332. https://doi.org/10.3390/antiox11020332

Ming H, Li B, Jiang J, Qin S, Nice EC, He W, Lang T, Huang C. Protein degradation: expanding the toolbox to restrain cancer drug resistance. J Hematol Oncol, 2023; 16(1):6. https://doi.org/10.1186/s13045-023-01398-5

Bulatov E, Ciulli A. Targeting Cullin-RING E3 ubiquitin ligases for drug discovery: structure, assembly and small-molecule modulation. Biochem, 2015; 467(3):365-86. https://doi.org/10.1042/BJ20141450

Muhammed MT, Esin AY. Pharmacophore modeling in drug discovery: methodology and current status. J Turk Chem Soc A Chem, 2021; 8(3):749-62. https://doi.org/10.18596/jotcsa.927426

Meng XY, Zhang HX, Mezei M, Cui M. Molecular docking: a powerful approach for structure-based drug discovery. Curr Comput Aided Drug Des, 2011; 7(2):146-57. https://doi.org/10.2174/157340911795677602

Mekky AE, Sanad SM, Abdelfattah AM. Tandem synthesis, antibacterial evaluation and SwissADME prediction study of new bis (1, 3, 4-oxadiazoles) linked to arene units. Mendeleev Commun. 2022; 32(5):612-4. https://doi.org/10.1016/j.mencom.2022.09.014

Ortmann B, Druker J, Rocha S. Cell cycle progression in response to oxygen levels. Cell Mol Life Sci, 2014; 71(18):3569-82. https://doi.org/10.1007/s00018-014-1645-9

Rabinowitz MH. Inhibition of hypoxia-inducible factor prolyl hydroxylase domain oxygen sensors: tricking the body into mounting orchestrated survival and repair responses. J Med Chem, 2013; 56(23):9369-402. https://doi.org/10.1021/jm400386j

Soares P, Gadd MS, Frost J, Galdeano C, Ellis L, Epemolu O, Rocha S, Read KD, Ciulli A. Group-based optimization of potent and cell-active inhibitors of the von hippel-lindau (VHL) E3 ubiquitin ligase: structure-activity relationships leading to the chemical probe (2S,4R)-1-((S)-2-(1-Cyanocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (VH298). J Med Chem, 2018; 61(2):599-618. https://doi.org/10.1021/acs.jmedchem.7b00675

Semenza GL, Wang GL. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol, 1992; 12(12):5447. https://doi.org/10.1128/MCB.12.12.5447

Semenza GL. HIF-1 and mechanisms of hypoxia sensing. Curr Opin Cell Biol, 2001; 13(2):167-71. https://doi.org/10.1016/S0955-0674(00)00194-0

Song C, Jiang Y, Cai W, Cheng K, Chen R, Qiu J, Hao Q, Liu Z. 2023. Epimedium/Icariin promotes angiogenesis through HIF-1 signaling pathway. Research Square [Online]. Available via https://www.researchsquare.com/article/rs-2765468/v1 (Accessed 10 May 2023). https://doi.org/10.21203/rs.3.rs-2765468/v1

Swaroop AK, Esakkimuthukumar M, Patnaik SK, Vasanth P, Jeyaprakash MR, Jawahar N, Jubie S. Dual modulation of IL-6 pathway by flavonoid metal complex as immune boosters for SARS-CoV-2 therapy. ECS Transactions, 2022; 107(1):9771. https://doi.org/10.1149/10701.9771ecst

Szklarczyk D, Franceschini A, Wyder S, Forslund K, Heller D, Huerta-Cepas J, Simonovic M, Roth A, Santos A, Tsafou KP, Kuhn M. STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic acids Res, 2015; 43(D1):D447-52. https://doi.org/10.1093/nar/gku1003

Szklarczyk D, Kirsch R, Koutrouli M, Nastou K, Mehryary F, Hachilif R, Gable AL, Fang T, Doncheva NT, Pyysalo S, Bork P, Jensen LJ, von Mering C. The STRING database in 2023: protein-protein association networks and functional enrichment analyses for any sequenced genome of interest. Nucleic Acids Res, 2023; 51(D1):D638-46. https://doi.org/10.1093/nar/gkac1000

Powell S, Forslund K, Szklarczyk D, Trachana K, Roth A, Huerta-Cepas J, Gabaldón T, Rattei T, Creevey C, Kuhn M, Jensen LJ, von Mering C, Bork P. eggNOG v4.0: nested orthology inference across 3686 organisms. Nucleic Acids Res, 2014; 42(Database issue):D231-9.

Pirhadi S, Damghani T, Avestan MS, Sharifi S. Dual potent c-Met and ALK inhibitors: from common feature pharmacophore modeling to structure based virtual screening. J Recept Signal Transduct Res, 2020; 40(4):357-64. https://doi.org/10.1093/nar/gkt1253

Qureshi KA, Mohammed SAA, Khan O, Ali HM, El-Readi MZ, Mohammed HA. Cinnamaldehyde-based self-nanoemulsion (CA-SNEDDS) accelerates wound healing and exerts antimicrobial, antioxidant, and anti-inflammatory effects in rats' skin burn model. Molecules, 2022; 27(16):5225. https://doi.org/10.3390/molecules27165225

Tanimoto K, Makino Y, Pereira T, Poellinger L. Mechanism of regulation of the hypoxia-inducible factor-1α by the von Hippel-Lindau tumor suppressor protein. EMBO J, 2000; 19(16):4298-309. https://doi.org/10.1093/emboj/19.16.4298

Quazi S, Malik J, Suman KS, Capuzzo AM, Haider Z. Discovery of potential drug-like compounds against Viral protein (VP40) of Marburg Virus using pharmacophoric based virtual screening from ZINC database. BioRxiv, 2021; 2021-05. https://doi.org/10.1101/2021.05.13.444037

Viana Nunes AM, das Chagas Pereira de Andrade F, Filgueiras LA, de Carvalho Maia OA, Cunha RLOR, Rodezno SVA, Maia Filho ALM, de Amorim Carvalho FA, Braz DC, Mendes AN. preADMET analysis and clinical aspects of dogs treated with the Organotellurium compound RF07: a possible control for canine visceral leishmaniasis? Environ Toxicol Pharmacol, 2020; 80:103470. https://doi.org/10.1016/j.etap.2020.103470

Article Metrics
94 Views 56 Downloads 150 Total

Year

Month

Related Search

By author names